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Muñoz-Islas E, Santiago-SanMartin ED, Mendoza-Sánchez E, Torres-Rodríguez HF, Ramírez-Quintanilla LY, Peters CM, Jiménez-Andrade JM. Long-term effects of gestational diabetes mellitus on the pancreas of female mouse offspring. World J Diabetes 2024; 15:758-768. [PMID: 38680692 PMCID: PMC11045410 DOI: 10.4239/wjd.v15.i4.758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/29/2024] [Accepted: 03/11/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Prolonged fetal exposure to hyperglycemia may increase the risk of developing abnormal glucose metabolism and type-2 diabetes during childhood, adolescence, and adulthood; however, the mechanisms by which gestational diabetes mellitus (GDM) predisposes offspring to metabolic disorders remain unknown. AIM To quantify the nerve axons, macrophages, and vasculature in the pancreas from adult offspring born from mouse dams with GDM. METHODS GDM was induced by i.p. administration of streptozotocin (STZ) in ICR mouse dams. At 12 wk old, fasting blood glucose levels were determined in offspring. At 15 wk old, female offspring born from dams with and without GDM were sacrificed and pancreata were processed for immunohistochemistry. We quantified the density of sensory [calcitonin gene-related peptide (CGRP)] and tyrosine hydroxylase (TH) axons, blood vessels (endomucin), and macro-phages (CD68) in the splenic pancreas using confocal microscopy. RESULTS Offspring mice born from STZ-treated dams had similar body weight and blood glucose values compared to offspring born from vehicle-treated dams. However, the density of CGRP+ and TH+ axons, endomucin+ blood vessels, and CD68+ macrophages in the exocrine pancreas was significantly greater in offspring from mothers with GDM vs control offspring. Likewise, the microvasculature in the islets was significantly greater, but not the number of macrophages within the islets of offspring born from dams with GDM compared to control mice. CONCLUSION GDM induces neuronal, vascular, and inflammatory changes in the pancreas of adult progeny, which may partially explain the higher propensity for offspring of mothers with GDM to develop metabolic diseases.
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Affiliation(s)
- Enriqueta Muñoz-Islas
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Edgar David Santiago-SanMartin
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Eduardo Mendoza-Sánchez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Héctor Fabián Torres-Rodríguez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | | | - Christopher Michael Peters
- Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, NC 27101, United States
| | - Juan Miguel Jiménez-Andrade
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
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Munoz-Islas E, Elizondo-Martinez CE, Gutierrez-Lopez M, Acosta-Gonzalez RI, Zaga-Clavellina V, Helguera-Repetto AC, Ramirez-Rosas MB, Romero-Sandoval EA, Jimenez-Andrade JM. Effect of Experimental Gestational Diabetes Mellitus on Mechanical Sensitivity, Capsaicin-Induced Pain Behaviors and Hind Paw Glabrous Skin Innervation of Male and Female Mouse Offspring. J Pain Res 2021; 14:1573-1585. [PMID: 34103982 PMCID: PMC8180275 DOI: 10.2147/jpr.s313467] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/11/2021] [Indexed: 01/13/2023] Open
Abstract
Purpose Gestational diabetes mellitus (GDM) induces cardiovascular and metabolic disturbances in offspring. However, the effects of GDM in pain processing in offspring and whether male and female offspring are equally affected is not well known. Thus, we determined: i) whether GDM in mice affects offspring hindpaw mechanical sensitivity, capsaicin-induced spontaneous pain-like behaviors, and epidermal nerve fiber density (ENFD); and ii) whether there is sexual dimorphism in these parameters in offspring from GDM dams. Methods GDM was induced in pregnant ICR mice via i.p. streptozotocin (STZ). Then, glucose levels from dams and offspring were determined. Male and female offspring 2–3 months of age were evaluated for: a) baseline mechanical sensitivity of the hind paw by using von Frey filaments; b) number of flinches and time spent guarding induced by intraplantar capsaicin (0.1%); and c) density of PGP-9.5 and CGRP axons in the epidermis from the hind paw glabrous skin. Results Prepartum levels of glucose in STZ-treated dams were significantly increased compared to vehicle-treated dams; however, GDM or vehicle offspring displayed normal and similar blood glucose levels. Male and female GDM offspring showed significantly greater mechanical sensitivity and capsaicin-induced pain behaviors compared to vehicle offspring. Male GDM offspring displayed a slightly more intense nociceptive phenotype in the capsaicin test. PGP-9.5 and CGRP ENFD in hind paw glabrous skin were greater in male and female GDM offspring versus their controls. Sexual dimorphism was generally not observed in GDM offspring in most of the studied parameters. Conclusion These results suggest GDM induced greater pain-like behaviors in adult offspring regardless of sex along with an increased ENFD of PGP-9.5 and CGRP in the hind paw glabrous skin. We show that GDM peripheral neuropathy differs from diabetic peripheral neuropathy acquired in adulthood and set the foundation to further study this in human babies exposed to GDM.
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Affiliation(s)
- Enriqueta Munoz-Islas
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | | | - Mariela Gutierrez-Lopez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | - Rosa Issel Acosta-Gonzalez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | - Veronica Zaga-Clavellina
- Departamento de Fisiología y Desarrollo Celular, Instituto Nacional de Perinatología, Ciudad de México, Mexico
| | | | - Martha Beatriz Ramirez-Rosas
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | | | - Juan Miguel Jimenez-Andrade
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
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Brain Development in Infants of Mothers With Gestational Diabetes Mellitus: A Diffusion Tensor Imaging Study. J Comput Assist Tomogr 2020; 44:947-952. [PMID: 33196602 DOI: 10.1097/rct.0000000000001110] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The objective of this study was to investigate clinical neurocognitive performance and microstructural white matter (WM) alterations in infants of mothers with gestational diabetes mellitus (GDM) using diffusion tensor imaging. MATERIALS AND METHODS Infants (corrected gestational age, 33.42-36.00 weeks) of mothers with GDM (n = 31) and gestational age- and sex-matched unexposed controls (n = 31) accomplished 3-T diffusion tensor imaging scans and neurocognitive tests. Diffusion tensor imaging measures, mainly referring to fractional anisotropy (FA) values, were compared between 2 groups, and within-group analysis of correlation between FA values and neurocognitive testing outcomes in GDM-exposed infants was conducted subsequently. RESULTS Fractional anisotropy was significantly decreased in the splenium of corpus callosum, posterior limb of internal capsule, thalamus in infants of mothers with GDM when compared with controls (P < 0.05), reflecting microstructural WM abnormalities in the GDM group. Decreased FA was associated with worse neurocognitive performance in the exposed group (P < 0.05). CONCLUSIONS Individuals of mothers with GDM showed microstructural WM abnormalities in different brain regions, which were significantly related to worse neurocognitive performance. This might reveal that GDM directly insults the brain development of the offspring.
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Gargiulo-Monachelli G, Meyer M, Lara A, Garay L, Lima A, Roig P, De Nicola AF, Gonzalez Deniselle MC. Comparative effects of progesterone and the synthetic progestin norethindrone on neuroprotection in a model of spontaneous motoneuron degeneration. J Steroid Biochem Mol Biol 2019; 192:105385. [PMID: 31150830 DOI: 10.1016/j.jsbmb.2019.105385] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/21/2019] [Accepted: 05/26/2019] [Indexed: 12/12/2022]
Abstract
The Wobbler mouse has been proposed as an experimental model of the sporadic form of amyotrophic lateral sclerosis (ALS). The administration of natural progesterone (PROG) to Wobbler mice attenuates neuropathology, inhibits oxidative stress, enhances the expression of genes involved in motoneuron function, increases survival and restores axonal transport. However, current pharmacological treatments for ALS patients are still partially effective. This encouraged us to investigate if the synthetic progestin norethindrone (NOR), showing higher potency than PROG and used for birth control and hormone therapy might also afford neuroprotection. Two-month-old Wobbler mice (wr/wr) were left untreated or received either a 20 mg pellet of PROG or a 1 mg pellet of NOR for 18 days. Untreated control NFR/NFR mice (background strain for Wobbler) were also employed. Wobblers showed typical clinical and spinal cord abnormalities, while these abnormalities were normalized with PROG treatment. Surprisingly, we found that NOR did not increase immunoreactivity and gene expression for choline-acetyltransferase, drastically decreased GFAP + astrogliosis, favored proinflammatory mediators, promoted the inflammatory phenotype of IBA1+ microglia, increased the receptor for advanced glycation end products (RAGE) mRNA and protein expression and the activity of nitric oxide synthase (NOS)/NADPH diaphorase in the cervical spinal cord. Additionally, NOR treatment produced atrophy of the thymus. The combined negative effects of NOR on clinical assessments (forelimb atrophy and rotarod performance) suggest a detrimental effect on muscle trophism and motor function. These findings reinforce the evidence that the type of progestin used for contraception, endometriosis or replacement therapy, may condition the outcome of preclinical and clinical studies targeting neurodegenerative diseases.
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Affiliation(s)
- Gisella Gargiulo-Monachelli
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Maria Meyer
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Agustina Lara
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Laura Garay
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Depto. de Bioquímica Humana, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina
| | - Analia Lima
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Paulina Roig
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Alejandro F De Nicola
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Depto. de Bioquímica Humana, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina
| | - Maria Claudia Gonzalez Deniselle
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Depto. de Ciencias Fisiológicas, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina.
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Piazza FV, Segabinazi E, de Meireles ALF, Mega F, Spindler CDF, Augustin OA, Salvalaggio GDS, Achaval M, Kruse MS, Coirini H, Marcuzzo S. Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus. Cell Mol Neurobiol 2019; 39:401-414. [PMID: 30739252 PMCID: PMC11469913 DOI: 10.1007/s10571-019-00658-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 01/30/2019] [Indexed: 12/14/2022]
Abstract
Maternal diabetes constitutes an unfavorable intrauterine environment for offspring development. Although it is known that diabetes can cause brain alterations and increased risk for neurologic disorders, the relationship between neuroimmune activation, brain changes, and neurodevelopment deficits in the offspring remains unclear. In order to elucidate the short- and long-term biological basis of the developmental outcomes caused by the severe uncontrolled maternal hyperglycemia, we studied apoptosis, neurogenesis, and neuroinflammation pathways in the hippocampus of neonates and young rats born to diabetic dams. Diabetes was induced on gestational day 5 by an injection of streptozotocin. Evaluations of milestones, body growth, and inhibitory avoidance were performed to monitor the offspring development and behavior. Hippocampal modifications were studied through cellular survival by BrdU in the dentate gyrus, expression of apoptosis-regulatory proteins (procaspase 3, caspase 3, and Bcl-2), BDNF, and neuroinflammatory modulation by interleukins, MHC-I, MHC-II, Iba-1, and GFAP proteins. Severe maternal diabetes caused microsomia and neurodevelopmental delay in pups and decrease of Bcl-2, procaspase 3, and caspase 3 in the hippocampus. Moreover, in a later stage of development, it was found an increase of TNF-α and a decrease of procaspase 3, caspase 3, MHC-I, IL-1β, and BDNF in the hippocampus, as well as impairment in cellular survival in the dentate gyrus. This study showed significant short- and long-term commitments on the development, apoptosis, cell survival, and neuroinflammation in the offspring hippocampus induced by severe uncontrolled maternal hyperglycemia. The data reinforce the need for treatment of maternal hyperglycemic states during pregnancy and breast-feeding.
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Affiliation(s)
- Francele Valente Piazza
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil.
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil.
| | - Ethiane Segabinazi
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
| | - André Luís Ferreira de Meireles
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Filipe Mega
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Christiano de Figueiredo Spindler
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Otávio Américo Augustin
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Gabriela Dos Santos Salvalaggio
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Matilde Achaval
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Maria Sol Kruse
- Laboratorio de Neurobiología, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Héctor Coirini
- Laboratorio de Neurobiología, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
- Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG, Buenos Aires, Argentina
| | - Simone Marcuzzo
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil
- Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil
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Rosa AP, Mescka CP, Catarino FM, de Castro AL, Teixeira RB, Campos C, Baldo G, Graf DD, de Mattos-Dutra A, Dutra-Filho CS, da Rosa Araujo AS. Neonatal hyperglycemia induces cell death in the rat brain. Metab Brain Dis 2018; 33:333-342. [PMID: 29260360 DOI: 10.1007/s11011-017-0170-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 12/11/2017] [Indexed: 02/06/2023]
Abstract
Several studies have examined neonatal diabetes, a rare disease characterized by hyperglycemia and low insulin levels that is usually diagnosed in the first 6 month of life. Recently, the effects of diabetes on the brain have received considerable attention. In addition, hyperglycemia may perturb brain function and might be associated with neuronal death in adult rats. However, few studies have investigated the damaging effects of neonatal hyperglycemia on the rat brain during central nervous system (CNS) development, particularly the mechanisms involved in the disease. Thus, in the present work, we investigated whether neonatal hyperglycemia induced by streptozotocin (STZ) promoted cell death and altered the levels of proteins involved in survival/death pathways in the rat brain. Cell death was assessed using FluoroJade C (FJC) staining and the expression of the p38 mitogen-activated protein kinase (p38), phosphorylated-c-Jun amino-terminal kinase (p-JNK), c-Jun amino-terminal kinase (JNK), protein kinase B (Akt), phosphorylated-protein kinase B (p-Akt), glycogen synthase kinase-3β (Gsk3β), B-cell lymphoma 2 (Bcl2) and Bcl2-associated X protein (Bax) protein were measured by Western blotting. The main results of this study showed that the metabolic alterations observed in diabetic rats (hyperglycemia and hypoinsulinemia) increased p38 expression and decreased p-Akt expression, suggesting that cell survival was altered and cell death was induced, which was confirmed by FJC staining. Therefore, the metabolic conditions observed during neonatal hyperglycemia may contribute to the harmful effect of diabetes on the CNS in a crucial phase of postnatal neuronal development.
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Affiliation(s)
- Andrea Pereira Rosa
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 (Anexo), Porto Alegre, RS, 90035-003, Brazil.
| | - Caroline Paula Mescka
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Felipe Maciel Catarino
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 (Anexo), Porto Alegre, RS, 90035-003, Brazil
| | - Alexandre Luz de Castro
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Rayane Brinck Teixeira
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Cristina Campos
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Guilherme Baldo
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Débora Dalmas Graf
- Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Angela de Mattos-Dutra
- Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Carlos Severo Dutra-Filho
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 (Anexo), Porto Alegre, RS, 90035-003, Brazil
| | - Alex Sander da Rosa Araujo
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Meyer M, Garay LI, Kruse MS, Lara A, Gargiulo-Monachelli G, Schumacher M, Guennoun R, Coirini H, De Nicola AF, Gonzalez Deniselle MC. Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration. J Steroid Biochem Mol Biol 2017; 174:201-216. [PMID: 28951257 DOI: 10.1016/j.jsbmb.2017.09.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 09/08/2017] [Accepted: 09/21/2017] [Indexed: 01/29/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. The Wobbler (WR) mouse is a preclinical model sharing neuropathological similarities with human ALS. We have shown that progesterone (PROG) prevents the progression of motoneuron degeneration. We now studied if allopregnanolone (ALLO), a reduced metabolite of PROG endowed with gabaergic activity, also prevents WR neuropathology. Sixty-day old WRs remained untreated or received two steroid treatment regimens in order to evaluate the response of several parameters during early or prolonged steroid administration. ALLO was administered s.c. daily for 5days (4mg/kg) or every other day for 32days (3, 3mg/kg), while another group of WRs received a 20mg PROG pellet s.c. for 18 or 60days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5α-DHP), whereas PROG treatment increased PROG, 5α-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5α-DHP than controls. In the cervical spinal cord we studied markers of oxidative stress or associated to trophic responses. These included nitric oxide synthase (NOS) activity, motoneuron vacuolation, MnSOD immunoreactivity (IR), brain derived neurotrophic factor (BDNF) and TrkB mRNAs, p75 neurotrophin receptor (p75NTR) and, cell survival or death signals such as pAKT and the stress activated kinase JNK. Untreated WRs showed a reduction of MnSOD-IR and BDNF/TrkB mRNAs, associated to high p75NTR in motoneurons, neuronal and glial NOS hyperactivity and neuronal vacuolation. Also, low pAKT, mainly in young WRs, and a high pJNK in the old stage characterized WŔs spinal cord. Except for MnSOD and BDNF, these alterations were prevented by an acute ALLO treatment, while short-term PROG elevated MnSOD. Moreover, after chronic administration both steroids enhanced MnSOD-IR and BDNF mRNA, while attenuated pJNK and NOS in glial cells. Long-term PROG also increased pAKT and reduced neuronal NOS, parameters not modulated by chronic ALLO. Clinically, both steroids improved muscle performance. Thus, ALLO was able to reduce neuropathology in this model. Since high oxidative stress activates p75NTR and pJNK in neurodegeneration, steroid reduction of these molecules may provide adequate neuroprotection. These data yield the first evidence that ALLO, a gabaergic neuroactive steroid, brings neuroprotection in a model of motoneuron degeneration.
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Affiliation(s)
- Maria Meyer
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Laura I Garay
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina
| | - María Sol Kruse
- Laboratory of Neurobiology, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Agustina Lara
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Gisella Gargiulo-Monachelli
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Michael Schumacher
- U1195 INSERM and University Paris Sud: "Neuroprotective, Neuroregenerative and Remyelinating Small Molecules", 94276, Kremlin-Bicêtre, France
| | - Rachida Guennoun
- U1195 INSERM and University Paris Sud: "Neuroprotective, Neuroregenerative and Remyelinating Small Molecules", 94276, Kremlin-Bicêtre, France
| | - Hector Coirini
- Laboratory of Neurobiology, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina
| | - Alejandro F De Nicola
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina
| | - Maria Claudia Gonzalez Deniselle
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Ciencias Fisiológicas, Facultad de Medicina, Universidad de, Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina.
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Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring. Mol Neurodegener 2017; 12:57. [PMID: 28768549 PMCID: PMC5541692 DOI: 10.1186/s13024-017-0198-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 07/24/2017] [Indexed: 12/11/2022] Open
Abstract
Background Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited. Methods Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates. Brain atrophy, neuronal morphology, tau phosphorylation, proliferation and neurogenesis were assessed in the short term (P7) and in the early adulthood (10 weeks) and cognitive function was also analyzed in the long-term. Results Central complications in DMO were still detected in the adulthood, including cortical and hippocampal thinning due to synaptic loss and neuronal simplification, increased tau hyperphosphorylation, and diminished cell proliferation and neurogenesis. Additionally, maternal diabetes increased the long-term susceptibility to spontaneous central bleeding, inflammation and cognition impairment in the offspring. On the other hand, intracerebroventricular insulin administration to neonates significantly reduced observed alterations. Moreover, non-invasive intranasal insulin reversed central atrophy and tau hyperphosphorylation, and rescued central proliferation and neurogenesis. Vascular damage, inflammation and cognitive alterations were also comparable to their counterparts born to nondiabetic mice, supporting the utility of this pathway to access the central nervous system. Conclusions Our data underlie the long-term effects of central complications in DMO. Moreover, observed improvement after insulin treatment opens the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes, and who may benefit from more individualized treatments.
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Impairment of synaptic development in the hippocampus of diabetic Goto-Kakizaki rats. Int J Dev Neurosci 2016; 53:58-67. [PMID: 27444810 DOI: 10.1016/j.ijdevneu.2016.07.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 06/30/2016] [Accepted: 07/17/2016] [Indexed: 12/28/2022] Open
Abstract
Insulin receptor signaling has been shown to regulate essential aspects of CNS function such as synaptic plasticity and neuronal survival. To elucidate its roles during CNS development in vivo, we examined the synaptic and cognitive development of the spontaneously diabetic Goto-Kakizaki (GK) rats in the present study. GK rats are non-obese models of type 2 diabetes established by selective inbreeding of Wistar rats based on impaired glucose tolerance. Though they start exhibiting only moderate hyperglycemia without changes in plasma insulin levels from 3 weeks postnatally, behavioral alterations in the open-field as well as significant impairments in memory retention compared with Wistar rats were observed at 10 weeks and were worsened at 20 weeks. Alterations in insulin receptor signaling and signs of insulin resistance were detected in the GK rat hippocampus at 3 weeks, as early as in other insulin-responsive peripheral tissues. Significant reduction of an excitatory postsynaptic scaffold protein, PSD95, was found at 5w and later in the hippocampus of GK rats due to the absence of a two-fold developmental increase of this protein observed in Wistar control rats between 3 and 20w. In the GK rat hippocampus, NR2A which is a NMDA receptor subunit selectively anchored to PSD95 was also reduced. In contrast, both NR2B and its anchoring protein, SAP102, showed similar developmental profiles in Wistar and GK rats with expression peaks at 2 and 3w. The results suggest that early alterations in insulin receptor signaling in the GK rat hippocampus may affect cognitive performance by suppressing synaptic maturation.
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Kruse MS, Vega MC, Rey M, Coirini H. Sex differences in LXR expression in normal offspring and in rats born to diabetic dams. J Endocrinol 2014; 222:53-60. [PMID: 24824431 DOI: 10.1530/joe-14-0054] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Gestational diabetes (GD) alters normal fetal development and is related to a diabetogenic effect in the progeny. Liver X receptors (LXRs) are considered to be potential drug targets for the regulation, treatment, or prevention of diabetes. The aim of this study was to evaluate early and late changes of LXR in the hippocampus and hypothalamus of the male and female offspring of control (CO) and diabetic (DO) mothers. We used an experimental model of streptozotocin-induced GD to assess the protein expression of LXRα (NR1H3) and LXRβ (NR1H2) by western blotting. The tissues were obtained from CO and DO animals at postnatal day 1 (1D), day 10 (10D), and day 35 (35D) and 9 months (9M). In CO, the LXR expression showed significant differences among the groups, which were tissue- and receptor-specific (P<0.05). Sex differences in CO were found only in the hypothalamus for LXRβ expression at 35D and 9M (P<0.05). When CO and DO were compared, differences between them were observed in the majority of the studied groups at 1D (male hippocampus, LXRα 31% and LXRβ 161%; female hippocampus, LXRβ 165%; male hypothalamus, LXRβ 182%; and female hypothalamus, LXRα 85%; P<0.05). However, these differences disappeared later with the exception of LXRβ expression in the male hypothalamus (P<0.05). The area under the curve during the glucose tolerance test correlated negatively with LXRβ in CO but not in DO animals. Moreover, in a male DO subpopulation this correlation was positive as it occurs in intolerant animals. These results indicate that GD affects hypothalamic LXR expression differently in male and female offspring.
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Affiliation(s)
- María Sol Kruse
- Laboratorio de NeurobiologíaInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, ArgentinaDepartamento de Bioquímica HumanaFacultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG Ciudad Autónoma de Buenos Aires, ArgentinaFacultad de Ciencias MedicasUniversidad Católica de Cuyo, Rivadavia, Provincia de San Juan, Argentina
| | - María Cristina Vega
- Laboratorio de NeurobiologíaInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, ArgentinaDepartamento de Bioquímica HumanaFacultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG Ciudad Autónoma de Buenos Aires, ArgentinaFacultad de Ciencias MedicasUniversidad Católica de Cuyo, Rivadavia, Provincia de San Juan, Argentina
| | - Mariana Rey
- Laboratorio de NeurobiologíaInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, ArgentinaDepartamento de Bioquímica HumanaFacultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG Ciudad Autónoma de Buenos Aires, ArgentinaFacultad de Ciencias MedicasUniversidad Católica de Cuyo, Rivadavia, Provincia de San Juan, Argentina
| | - Héctor Coirini
- Laboratorio de NeurobiologíaInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, ArgentinaDepartamento de Bioquímica HumanaFacultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG Ciudad Autónoma de Buenos Aires, ArgentinaFacultad de Ciencias MedicasUniversidad Católica de Cuyo, Rivadavia, Provincia de San Juan, ArgentinaLaboratorio de NeurobiologíaInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, ArgentinaDepartamento de Bioquímica HumanaFacultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG Ciudad Autónoma de Buenos Aires, ArgentinaFacultad de Ciencias MedicasUniversidad Católica de Cuyo, Rivadavia, Provincia de San Juan, ArgentinaLaboratorio de NeurobiologíaInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, ArgentinaDepartamento de Bioquímica HumanaFacultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG Ciudad Autónoma de Buenos Aires, ArgentinaFacultad de Ciencias MedicasUniversidad Católica de Cuyo, Rivadavia, Provincia de San Juan, Argentina
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Jing YH, Song YF, Yao YM, Yin J, Wang DG, Gao LP. Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF-I signals. Int J Dev Neurosci 2014; 37:15-20. [PMID: 24953263 DOI: 10.1016/j.ijdevneu.2014.06.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 06/12/2014] [Accepted: 06/12/2014] [Indexed: 01/26/2023] Open
Abstract
Hyperglycemia is an essential risk factor for mothers and fetuses in gestational diabetes. Clinical observation has indicated that the offspring of mothers with diabetes shows impaired somatosensory function and IQ. However, only a few studies have explored the effects of hyperglycemia on fetal brain development. Neurodevelopment is susceptible to environmental conditions. Thus, this study aims to investigate the effects of maternal hyperglycemia on fetal brain development and to evaluate insulin and insulin-like growth factor-I (IGF-I) signals in fetal brain under hyperglycemia or controlled hyperglycemia. At day 1 of pregnancy, gestational rats were intraperitoneally injected with streptozocin (60 mg/kg). Some of the hyperglycemic gestational rats were injected with insulin (20 IU, two times a day) to control hyperglycemia; the others were injected with saline of equal volume. The gestational rats were sacrificed at days 14, 16, and 18 of embryo development. The dendritic spines of subplate cortex neurons in the fetal brain were detected by Golgi-Cox staining. The mRNA levels of insulin receptors (IRs) and IGF-IR in the fetal brain were measured using qRT-PCR. The protein levels of synaptophysin, IR, and IGF-IR in the fetal brain were detected by western blot. No significant difference in fetal brain formation was observed between the maternal hyperglycemic group and insulin-treated group. By contrast, obvious retardation of dendritic development in the fetus was observed in the maternal hyperglycemic group. Similarly, synaptophysin expression was lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. The mRNA and protein expression levels of IRs in the fetal brain were higher in the hyperglycemic group than in the insulin-treated group. By contrast, the levels of IGF-IR in the brain were lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. These results suggested that maternal hyperglycemia can retard dendritic development in the fetal brain and that these changes partially resulted from abnormal insulin/IGF-I signaling in the fetal brain.
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Affiliation(s)
- Yu-Hong Jing
- Institute of Anatomy and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, PR China; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, PR China.
| | - Yan-Feng Song
- Institute of Anatomy and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, PR China
| | - Ya-Ming Yao
- Institute of Anatomy and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, PR China
| | - Jie Yin
- Institute of Anatomy and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, PR China
| | - De-Gui Wang
- Institute of Anatomy and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, PR China
| | - Li-Ping Gao
- Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, PR China
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